NYU Expert Examines Emerging Agents in Colorectal Cancer

Jennifer Wu, MD

With the FDA approval of a novel therapy and the discovery of a possible biomarker to predict which patients are likely to respond to a PD-1 inhibitor, 2015 proved to be a positive year for the treatment paradigm of colorectal cancer (CRC).

The oral nucleoside TAS-102 (Lonsurf) was approved by the FDA in September for the treatment of patients with metastatic disease who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal antibody, if RAS wild-type. This provides a second single-agent option for patients, as regorafenib (Stivarga) was approved in 2012 for patients with metastatic disease who had prior therapy.

The TAS-102 approval was based on results from the phase III RECOURSE trial, which examined 800 patients with refractory metastatic CRC.¹ In the study, the overall survival (OS) for those who received TAS-102 was 7.1 months compared with 5.3 months with placebo (HR, 0.68; P <.0001). The median progression-free survival (PFS) in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR, 0.48; P <.0001).

Earlier this year, at the 2015 ASCO Annual Meeting, data showed that individuals with CRC who have high levels of deficiency in DNA mismatch repair (MMR) have a higher production of neo-antigens and are potential candidates for immunotherapy.² In the study, patients with MMR deficiencies who received pembrolizumab (Keytruda) had an objective response rate of 62% compared with 0% in patients with MMR-proficient tumors. These findings suggest that MMR could be a biomarker for PD-1 inhibition.

OncLive: What are some of the most promising emerging agents in CRC right now?

In an interview with OncLive, Jennifer Wu, MD, an assistant professor of Medicine in the Department of Medicine at Perlmutter Cancer Center and NYU Langone Medical Center, sheds light on TAS-102, as well as some emerging agents likely to play a role in the treatment of patients with CRC.Wu: Currently, there is a focus on two single agents. One is regorafenib, which is a non-chemotherapeutic agent that showed OS benefits in refractory CRC. The other one was actually approved in September—TAS-102&mdash;and, as a single agent, it also showed an OS benefit.

Both of these are oral agents and they have shown a pretty impressive survival benefit in similar patient populations, except that TAS-102 includes patients who had received prior regorafenib. The agents each have their own side effect profile.

I think those are very good choices for our patients now. We have two options, and the choice of one versus the other depends on patient preference, prior patience experience, or prior chemotherapy. We can choose one or the other. Sometimes, it is even possible to do it sequentially.

Secondly, we now have EGFR inhibitors for RAS and RAF wild-type patients. We have realized that it’s not adequate to just inhibit BRAF. In contrast to melanoma, we have EGFR feedback activation in CRC. If we just inhibit a single-agent BRAF inhibitor, it doesn’t really work.

Therefore, there are ongoing studies that combine both BRAF and EGFR inhibitors with pretty good results, although it is preliminary data. There are also data indicating that, by combining all 3 BRAF, MEK and EGFR inhibitors, patients had either stable disease or a response rate of 80% in the refractory setting.

There is also the fact that when patients are treated with therapy, they acquire resistance. Acquired resistance actually increases in patients with HER2 amplification, so there has been a study combining EGFR and HER2 agents in patients who have received 5 prior lines of therapy, and the response rate was 35%. That is pretty impressive.

Stem cell inhibitors are also being investigated in CRC. What can you share about this?

There are also some agents being combined with chemotherapy agents, such as a SYK inhibitor and an Hsp90 inhibitor. Although they are small studies, the OS is 16 months, and that is very exciting.This is the most exciting one to me. We understand that there are stem cells for all kinds of cancers, and there are a couple stem cell inhibitors that are ongoing with CRC treatment right now.

One of them inhibits a transcription factor in the stem cell pathway called Nanog. In patients who were positive for this biomarker, their PFS was approximately 16 weeks in fifth-line therapy versus 6 weeks in patients without the stem cell marker. It is a small study, but perhaps we now have a biomarker about stem cells.

Another study examined a stem cell inhibitor that inhibited STAT3 and β-catenin pathway when combined with an EGFR inhibitor in the second- or third-line setting. One group includes patients who have never been treated with an EGFR inhibitor before; the other group is made up of patients treated with EGFR inhibitors, but now in combination with the stem cell inhibitor.

The FDA has approved TAS-102 as a single agent. Is there interest in seeing what effects it could have in combination with other agents?

There were also exciting results presented at the 2015 ASCO Annual Meeting regarding clinical activity with immunotherapy in patients with MMR-deficient tumors. Can you comment on these findings?

In both groups, the control rate is approximately 40%. However, the patients who were treated before seemed to do better—both in disease control rate and PFS. That gave us an idea that, perhaps, stem cell inhibition is the way to go, especially for patients who have been previously treated with chemotherapy. I’m sure we are going to hear more about all of these above agents at upcoming conferences.We know that it was tested with oxaliplatin in preclinical models, and we also know that there was an abstract presented earlier this year where TAS-102 was combined with bevacizumab in refractory CRC, and it did have pretty high response rates, as well. I think that TAS-102 will be on the way to have novel combinations in the future, maybe not just with chemotherapy, but maybe more exciting stuff, such as stem cell inhibitors. It’s an open question.This is almost like a whole new door for us. If we have a DNA defect, the MMR enzyme comes in, corrects it, and DNA continues to replicate. It’s the same thing with cancer cells. When you have a deficiency in such an enzyme, the cancer cells cannot repair themselves very well. If we have an agent that sort of stops this enzyme from working even better, then we can stop the cancer cells from proliferating.

For patients who have MMR, their proliferation is not high because they keep having errors every time they replicate. The mutation load for such cancer cells is very high, so we know that the mutation rate here is 1500. In normal CRC cells, it is about 40. In immunotherapy in particular, this worked in patients who had higher mutational loads. Therefore, the MMR deficiency in CRC is a category where we believe immunotherapy would have some effect. In the study, all patients who had MMR-deficient genes had a response. It doesn’t matter if it’s CRC or non-CRC.

What other ongoing clinical trials are you anticipating the results of?

Now, we are in an era where immunotherapy allows us to focus not on organ-specific disease, but on molecular biology. It’s very provocative. The response rates are extremely high, and also the PFS rate has not even been reached in patients with MMR deficiency. I think that immunotherapy will be something very exciting, at least for this subgroup.There are multiple ongoing studies. We know the EGFR pathway goes down to RAF, RAS, and MEK. However, there is another pathway involving PI3K, AKT, and mTOR. There are definitely trials ongoing in PI3K, either for wild-type or mutant patients, where we see combinations of EGFR inhibitors with chemotherapy or with mTOR inhibitors. There is also a lot of excitement with PI3K inhibitors. We are in this era where colon cancer is no longer one disease. It’s based on the molecular biology where we have specific agents for those patients.

References

1. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909-1919.
2. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. J Clin Oncol. 2015;(suppl; abstr LBA100).